What are the reasons for negative values?

Four physiological reasons

Smaller alveolar dead space and inherent upward slope of phase III

Increase in the slope of phase III

Exaggerated alveolar PCO2 fluctuations during respiratory cycle due to increased CO2 production and decreased FRC which make it more likely to sample higher alveolar PCO2 (sampled as PETCO2 ) during expiration greater than mean PaCO2

Occurrence of phase IV

Negative (a-ET)PCO2 gradients:

Negative (a-ET)PC02 values were observed more than 30 yr ago by Nunn et al. during anesthesia although no explanation was offered.1 Fletcher et al. observed negative or zero (a-ET)PCO2 values in 12% of normal subjects during anesthesia and IPPV with large tidal volumes and low frequencies.2 Negative values were also observed during anesthesia in 50% of pregnant subjects,3 in 8.1% of patients after post-cardiac bypass (PCB)4 and in 50% of infants.5

Piper reviewed several studies with negative arterial to end-tidal CO2 differences in 1986 and concluded that the reasons for the remarkably pronounced disagreement between the experimental data of different studies cannot be definitely identified and suggested that it is desirable that more observational and experimental data become available in future to review this subject.6 Since then several studies have reported negative differences as stated above. The following possible mechanism have been postulated to explain observed (a-ET)PCO2 differences under various circumstances.

Large tidal volume and low frequency ventilation result in (i) better ventilation of dependent well-perfused alveoli which improves V/Q matching (small area of alveolar dead space as above in figure I). (ii) Gas emptying from slow alveoli to reach the mouth, whereas it would have remained in the airways with small frequent breaths. Under these circumstances the low V/Q areas (alveoli with higher PC02) make a more substantial contribution to the gas exchange. The net effect of these factors is to enable the terminal part of phase III to exceed mean PaC02, resulting in negative (a-ET)PC02.2

Alveolar PCO2 varies cyclically, being lowest at end-inspiration and highest at end-expiration. However, because of mixing in the heart and syringe, PaCO2 sampled at the radial artery is the spatial and temporal mean of alveolar PCO2 (Riley's physiological integrator) and therefore it is quite possible for PETCO2 to exceed the sampled PaCO2. The increased cardiac output and increased C02 production, reduced FRC and low compliance associated with pregnancy may result in greater cyclical variations in alveolar PCO2 during a respiratory cycle and also in more alveoli with long time constants. During expiration, PACO2 increases towards PVC02 (partial pressure of mixed venous C02) more rapidly in pregnant subjects because a larger amount of C02 is evolved into a lung which becomes smaller as expiration continues. Further, pregnant subjects resemble the obese in some features namely reduced FRC and low total compliance and hence may exhibit a biphasic slope reminiscent of phase IV of the nitrogen closing volume test. The PC02 of most alveolar gas is less than PaC02 but, in the terminal part of the expirate, PC02 rises rapidly and may exceed PaC02. The combined effect of these two mechanisms increases the slope of phase III (Figure 4) and the likelihood of sampling a PETCO2 greater than PaC02.3,7-12 The presence of a wide range of V/Q mismatching and reduced FRC may result in negative (a-ET)PC02 values in patients after cardiopulmonary bypass.4,7 Increased C02 production and reduced FRC may be responsible for the negative (a-ET)PCO2 values observed in infants.5

(a-ET)PCO2 may not reflect Alveolar Dead Space when phase III has a steeper slope

(a-ET)PCO2 could be zero or negative even in the presence of alveolar dead space

*This animation has been based on the concept as in reference 2.

(a-ET)CO2 gradient as an index of alveolar dead space:

Under normal circumstances, the PETCO2 (the CO2 recorded at the end of the breath which represents PCO2 from alveoli which empty last) is lower than PaCO2 (average of all alveoli) by 2-5 mmHg, in adults.1-8 The (a-ET)PCO2 gradient is due to the V/Q mismatch in the lungs (alveolar dead space) as a result of temporal, spatial, and alveolar mixing defects. In healthy children, the (a-ET)PCO2 gradient is smaller (-0.65-3 mm Hg) than in adults.9-14 This is due to a better V/Q matching, and hence a lower alveolar dead space in children than in the adults.9 The (a-ET)PCO2 / PaCO2 fraction is a measure of alveolar dead space, and changes in alveolar dead space correlate well with changes in (a-ET)PCO2.4 An increase in (a-ET)PCO2 suggests an increase in dead space ventilation. Hence (a-ET)PCO2 is an indirect estimate of V/Q mismatching of the lung.

However, (a-ET)PCO2 does not correlate with alveolar dead space in all circumstances. Changes in alveolar dead space correlate with (a-ET)PCO2 only when phase III is flat or has a minimal slope. In this case, the area (blue shaded color in the figure above) rectangular and PaCO2 > PETCO2. However, if phase III has a steeper slope, the terminal part of phase III may intercept the line representing PaCO2, resulting in either zero or negative (a-ET)PCO2 even in the presence of alveolar dead space. Therefore, the (a-ET)PCO2 is dependent both on alveolar dead space as well as factors that influence the slope of phase III. This implies that an increase in the alveolar dead space need not be always be associated with an increase in the (a-ET)PCO2. The (a-ET)PCO2 may remain the same if there is an associated increase in the slope of the phase III. For example, it has been observed during cardiac surgery that alveolar dead space was increased at the end of cardiopulmonary bypass but as the slope of phase III was also increased, there was no change in (a-ET)PCO2.15,16

Cardiac output and (a-ET)PCO2

Reduction in cardiac output and pulmonary blood flow result in a decrease in PETCO2 and an increase in (a-ET)PC02. Increases in cardiac output and pulmonary blood flow result in better perfusion of the alveoli and a rise in PETCO2.17,18 Consequently alveolar dead space is reduced as is (a-ET)C02 The decrease in (a-ET)PC02 is due to an increase in the alveolar C02 with a relatively unchanged arterial C02 concentration, suggesting better excretion of C02 into the lungs. The improved C02 excretion is due to better perfusion of upper parts of the lung.18 Askrog found an inverse linear correlation between pulmonary artery pressure and (a-ET)PC02.18 Thus, under conditions of constant lung ventilation, PETCO2 monitoring can be used as a monitor of pulmonary blood flow.17,19

PETCO2 and Cardiac output

Physiology of capnography

Bhavani Shankar Kodali MD

How does cardiac output affect PETCO2

Increases in cardiac output and pulmonary blood flow result in better perfusion of the alveoli and a rise in PETCO2.Under conditions of constant lung ventilation, PETCO2 monitoring can be used as a monitor of pulmonary blood flow

Cardiac output and (a-ET)PCO2

Reduction in cardiac output and pulmonary blood flow result in a decrease in PETCO2 and an increase in (a-ET)PC02.1,2 The percent decrease in PETCO2 directly correlated with the percent decrease in cardiac output (slope= 0.33, r2=0.82 in 24 patients undergoing aortic aneurysm surgery with constant ventilation).3 Also, the percent decrease in CO2 elimination correlated with the percent decrease in cardiac output similarly (slope=0.33, r2=0.84).3 The changes in PETCTO2 and CO2 elimination following hemodynamic perturbation were parallel. These findings suggest that decrease in PETCO2 quantitatively reflect the decreases in CO2 elimination.3

Increases in cardiac output and pulmonary blood flow result in better perfusion of the alveoli and a rise in PETCO2.1,2 Consequently alveolar dead space is reduced as is (a-ET)C02 The decrease in (a-ET)PC02 is due to an increase in the alveolar C02 with a relatively unchanged arterial C02 concentration, suggesting better excretion of C02 into the lungs. The improved C02 excretion is due to better perfusion of upper parts of the lung.2 Relationship between PETCO2 and pulmonary artery blood flow was studied during separation from cardiopulmonary bypass.4 This showed that PETCO2 is a useful index of pulmonary blood flow. A PETCO2 greater than 30 mm Hg was invariably associated with a cardiac output more than 4 L/min or a cardiac index > 2 L/min.4 Furthermore, when PETCO2 exceeded 34 mm Hg, pulmonary blood flow was more than 5 L/min (CI > 2.5 L).4

Thus, under conditions of constant lung ventilation, PETCO2 monitoring can be used as a monitor of pulmonary blood flow.4-8

Recently, using Fick's Principle, attempts were made to determine cardiac output non-invasively implementing periods of CO2 rebreathing during which CO2 partial pressure of oxygenated mixed venous blood was obtained from the measured exponential rise of the PET value. In addition, oxygen uptake, carbon dioxide elimination, end-tidal PCO2, oxygen saturation, and tidal volume were determined. The results are encouraging in patients with healthy lungs.9 Whereas the results are controversial when the lungs are diseased.10

Phase IV

Physiology of capnography

Phase IV

Occurs in obese patients and in pregnant subjects where thoracic compliance is reduced

Etiology

Slow alveoli empty out more evenly (expiratory flow rate is more constant) and the increase in PCO2 is spread more evenly over the tidal volume

Fast alveoli empty fast initially and then slow down. Most of the expirate leaves in the first second at almost constant PCO2. Towards the end of expiration, there is only a small amount of expired gas flow thereby increasing PCO2 steeply.

The combined result of these two emptying patterns is as follows

A terminal upswing is observed at the end of phase III under certain circumstances, such as during anesthesia/IPPV in obese patients and in pregnant subjects. The initial part of phase III is horizontal, or has a minimal slope, and lies below the level of PaCO2. The terminal part of phase III ascends steeply and may reach PaCO2. The terminal upswing, or rise, is known as phase IV because it resembles phase IV in the SBT-N2 curve.1,2 Phase IV of SBT-N2 is attributed to to airway closure.3,4 However, closure of dependent airways theoretically should cause a terminal downswing at the end of phase III in a capnogram rather than an upswing. This downswing ought to occur because, consequent to airway closure, the units in dependent regions (low V/Q units) containing high CO2 relative to nondependent zones (high V/Q units) no longer contribute to the expired gas and, therefore, should result in a decline in the overall CO2 concentration at the end of expiration.4 The mechanism responsible for phase IV (terminal rise) in capnograms recorded in obese subjects as well as in pregnant subjects is complex and may be explained on the basis of the expiratory characteristics of the fast and slow alveoli in these subjects.1,5

Based on the lung model studies, it has been suggested that, in obese subjects with healthy lungs, there may be two lung compartments with different mechanical and V/Q properties (fast and slow compartments).1,5 Lung model studies were also used to study the alveolar CO2 concentrations from fast and slow compartments during passive expiration where the expiratory flow patterns resembles a "die away" exponential function.1,5 The figure above shows alveolar PCO2 curves obtained from fast and slow compartments.

From the fast alveolar compartments, there is a rapid initial emptying of gases. The high initial expiratory flow rate implies that most of the gases leaving the alveoli has a rather constant FCO2 and is responsible for the near-horizontal initial part of phase III in CO2 trace. However, as the expiratory flow decreases towards the end of expiration, the CO2 content of the expired air increases markedly, producing a terminal steep rise or a ‘knee’ in the FCO2 tracing. This is because, in the later part of expiration, the delayed alveolar emptying results in higher FCO2 due to the continuous release of CO2 into the alveoli. Normally, the alveolar gases with high CO2 may remain within the airways (anatomical dead space) and are not analyzed by the CO2 sensor at the mouth. However, the use of large tidal volumes and low-frequency ventilation enables these gases to reach the mouth where the CO2 sensor registers high FCO2.

The slow compartments empty at a more even pace producing a positive slope from the beginning of phase III, as more time is allowed for CO2 to accumulate in the alveoli. As the expiratory flow rate decreases towards the end of expiration, the slope of phase III increases steadily.

The combined effect of the emptying characteristics of different alveoli determines the shape of the alveolar plateau in an capnogram during IPPV.

The low total thoracic compliance of obese patients is associated with rapid initial emptying of the lungs and phase III of the resulting capnogram predominantly resembles the one produced by the fast compartment: a near-horizontal phase III, or phase III with minimal slope and a terminal upswing (phase IV) similar to phase IV of the SBTN2 curve.

Pregnant subjects resemble obese subjects in some features, namely, reduced functional residual capacity (FRC) and low total thoracic compliance. Additionally, CO2 production is increased in pregnancy. Hence, phase IV may also occur in pregnant subjects during general anesthesia/IPPV with large tidal volumes.4,6-8 The presence of phase IV also contributes to the negative (a-ET)PCO2 values, where end-tidal PCO2 may exceed paCO2, which may be observed in obese and pregnant subjects.1,7-9

Determination of components of tidal volume using a capnogram

A volume capnogram can be used to understand how a capnogram can be related to a tidal volume and its components.

A horizontal line (red line in the figure) representing PaC02 (arterial blood sampled during the PETCO2 recordings) is drawn on the CO2 trace. The area under the curve, green area, is the volume of C02 in the breath and represents effective alveolar ventilation. The remaining area below the horizontal red line represents wasted ventilation (physiological dead space). A vertical line is constructed through phase II so that the two areas p and q are equal. Area orange represents anatomical dead space and area brown represents alveolar dead space. Therefore, physiological dead space is represented by area brown plus area orange.1-4